Field of the Invention
The present invention is in the field of organic chemistry. The present invention relates to an efficient process for the direct transformation of commercially available (3R,3′R,6′R)-lutein or unsaponified extracts of lutein from marigold flower petals containing 4-5% (3R,3′R)-zeaxanthin to (3R)-β-cryptoxanthin in 97% purity via (3R)-β-cryptoxanthin esters under very mild reaction conditions.
Related Art
The present invention is a unique modification of three earlier processes that have been reported for the conversion of commercially available (3R,3′R,6′R)-lutein to a mixture of (3R)-β-cryptoxanthin and (3R,6′R)-α-cryptoxanthin. The uniqueness of the present invention is based on the fact that several chemical reactions that allow the transformation of (3R,3R,6′R)-lutein to (3R)-β-cryptoxanthin have all been carried out in, a single step in a one pot reaction at room temperature. In, addition, the resulting (3R)-β-cryptoxanthin is in excess of 97% pure and is not accompanied by any significant amount of (3R,6′R)-α-cryptoxanthin. Further, the reaction conditions for this transformation can be adjusted to obtain any ratios of (3R)-β-cryptoxanthin to (3R,6′R)-α-cryptoxanthin.
The first process for the conversion of lutein to a mixture of (3R)-β-cryptoxanthin and (3R,6′R)-α-cryptoxanthin, was reported by Khachik in U.S. Pat. No. 6,911,564. This process involved conversion of lutein (1) containing approximately 5-7% (3R,3′R)-zeaxanthin (2) to a mixture of (3R)-β-cryptoxanthin (6) and (3R,6′R)-α-cryptoxanthin (7) via (3R,6′R)-anhydrolutein I ((3R,6′R)-3-Hydroxy-3′,4′-didehydro-β,γ-carotene) (3), (3R,6′R)-2′,3′-anhydrolutein II ((3R,6′R)-3-Hydroxy-2′,3′-didehydro-β,ε-carotenene) (4), and (3R)-3′,4′-anhydrolutein III ((3R)-3-Hydroxy-3′,4′-didehydro-β,β-carotene) (5) in one synthetic step by allylic deoxygenation with a strong acid and a hydride ion donor. The chemical structures of these carotenoids are shown in Scheme 1.

The chemical structures of (3R,3′R,6′R)-lutein, (3R,3′R)-zeaxanthin, anhydroluteins I, II, and III, (3R)-β-cryptoxanthin, and (3R,6′R)-α-cryptoxanthin. The systematic names of carotenoids are shown below their structures.
U.S. Pat. No. 6,911,564 also described a two-step alternative process. The first step converted lutein to a mixture of anhydroluteins I, II, and III at room temperature in the presence of an acid and in the second step, the isolated anhydroluteins were converted to (3R)-β-cryptoxanthin and (3R,6′R)-α-cryptoxanthin with a strong acid and a hydride ion donor.
As described in U.S. Pat. No. 6,911,564, the acid-catalyzed dehydration of lutein in a homogenous phase in a variety of solvents such as ethers (tetrahydrofuran, tert-butyl methyl ether), chlorinated solvents (dichloromethane, chloroform, 1,2-dichloroethane), acetone, and toluene at ambient temperature led to the formation of considerable amount of Z(cis)-isomers of anhydroluteins. In addition, under the conditions disclosed in U.S. Pat. No. 6,911,564, anhydrolutein I was the major product and anhydroluteins II and III were the minor products. Because anhydrolutein III was the precursor to (3R)-β-cryptoxanthin in the ionic hydrogenation step, a higher ratio of this carotenoid relative to anhydroluteins I and II was preferred. Therefore, according to U.S. Pat. No. 6,911,564 a mixture of (3R)-β-cryptoxanthin and (3R,6′R)-α-cryptoxanthin could be obtained in the ratio of 3:1.
In a second process described in U.S. Pat. No. 7,115,786, Khachik reported a modified two-step process for the dehydration of (3R,3′R,6′R)-lutein that significantly improved the ratio of anhydrolutein III (5) to anhydroluteins I (3) and II (4) and allowed the transformation of these lutein dehydration products to a mixture of (3R)-β-cryptoxanthin (6) and (3R,6′R)-α-cryptoxanthin (7) in the ratio of 3:1. In the first step according to U.S. Pat. No. 7,115,786, lutein was allowed to react with an alcohol, used as solvent, in the presence of a catalytic amount of an acid between 45-50° C. to give the corresponding 3′-alkyl ethers of lutein. Water and additional acid were then added to the mixture and the temperature was raised to 78-88° C. to convert the resulting lutein 3′-alkyl ethers to a mixture, of anhydroluteins I, II, and III, quantitatively (Scheme 2). At the beginning of this transformation, anhydrolutein I was the major product and anhydrolutein II and III were the minor products. As heating continued at 78-88° C., anhydroluteins I and II were partially isomerized to anhydrolutein III within 7-20 hours depending on the nature of the alcohol.

Dehydration of lutein to anhydrolutein III according to U.S. Pat. No. 7,115,786.
In the second step of U.S. Pat. No. 7,115,786, the resulting product, rich in anhydrolutein III, was allowed to react with about 1.3 equivalents of a hydride donor and about 3.5-4 equivalents of a strong organic acid in a chlorinated solvent at ambient temperature for about 1-5 hours to give a mixture of E/Z-(3R)-β-cryptoxanthin, E/Z-(3R,6′R)-α-cryptoxanthin, and minor quantities of unreacted anhydroluteins I and II.
According to a third process disclosed in U.S. Pat. No. 8,097,762, Khachik et al. developed an alternative route to the second step of U.S. Pat. No. 7,115,786 for making (3R)-β-cryptoxanthin and (3R,6′R)-α-cryptoxanthin from anhydroluteins that eliminated the use of chlorinated solvents and reagents such as trifluoroacetic acid, and hydride donors such as borane-amine complex. This was accomplished by heterogeneous or homogeneous regioselective catalytic hydrogenation of anhydroluteins as shown in Scheme 3. In addition, this process also employed a mixture of esterified luteins as the starting material to prepare anhydroluteins that were then transformed to (3R)-β-cryptoxanthin and (3R,6′R)-α-cryptoxanthin by regioselective catalytic hydrogenation. However, because strongly acidic conditions and high temperature were used, this transformation was accompanied by significant losses of the desired carotenoids.

Catalytic hydrogenation of anhydroluteins I, II, and III to (3R)-β-cryptoxanthin and (3R 6′R)-α-cryptoxanthin according to U.S. Pat. No. 8,097,762.
In all three processes, (3R)-β-cryptoxanthin is accompanied by significant amounts of (3R,6′R)-α-cryptoxanthin; therefore, a new and simplified methodology is needed that allows the direct transformation of lutein or unsaponified extracts of lutein from marigold flowers to (3R)-β-cryptoxanthin as the sole product under very mild conditions.